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A Bi-Adjuvant Senolytic Nanovaccine Modulating Dendritic Cell Senescence Ameliorates Aging-Related Metabolic
Qingxu Song1, Xiaoxue Du2, Wenbo Dong2
1Department of Spine Surgery, The First Hospital of Jilin University, Changchun, People's Republic of China.
Abstract:
Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno-antigen immunogenicity and age-related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial-enabled bi-adjuvant senolytic nanovaccine (CK5-GC-NV) by co-assembling CpG oligodeoxynucleotide with a fusion protein of the seno-antigen Gpnmb and a cationic spider silk protein variant (CK5). Beyond antigen delivery, the CK5 scaffold acts as an intrinsic senomodulator associated with the downregulation of mitotic kinases Aurka/b and a concomitant decrease in senescence-associated PI3K/AKT phosphorylation in DCs. This intervention attenuates aged DC phenotypes, restores antigen cross-presentation, and synergizes with CpG to elicit potent cytotoxic T-lymphocyte responses against senescent targets. Across multiple aging mouse models, CK5-GC-NV immunization orchestrated targeted clearance of Gpnmb+ senescent adipocytes, profoundly ameliorating metabolic dysfunction and extending lifespan. This multifunctional biomaterial platform integrates seno-antigen immunogenicity enhancement with the restoration of aged DC function, providing a promising proof-of-concept for antigen-directed gerotherapeutics.